Therapeutic compounds

Abstract

The invention provides compounds of formula (I), or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt, wherein R 1 , R 2 , R 3 , HET, n, Q, X, Y, and Z are as described herein; compositions thereof; and uses thereof including treating Type 2 diabetes.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt, wherein: 
 R 1  is —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —(C 1 -C 6 )arylalkyl, —NR a R b , hydroxy, cyano, aryl, or heteroaryl, wherein said —(C 1 -C 6 )alkyl, said aryl, or said heteroaryl is optionally substituted independently with one to three —COOH, —C(O)(C 1 -C 6 )alkoxy, —C(O)(C 1 -C 6 )alkyl, —C(O)NR a R b , cyano, halogen, nitro, trifluoromethyl, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —(C 3 -C 6 )cycloalkyl, or phenyl, wherein:  
 R a  and R b  are, independently, hydrogen, —(C 1 -C 6 )alkyl, aryl, or heteroaryl, or  
 R a  and R b , taken together with the nitrogen atom to which they are attached, form a four- to six-membered heterocyclic ring, wherein said ring optionally incorporates an additional one or two nitrogen, oxygen, or sulfur ring heteroatoms;  
 R 2  and R 3  are, independently, hydrogen, halogen, —(C 1 -C 6 )alkyl, or —(C 3 -C 8 )cycloalkyl;  
 Q is a covalent bond, —C(O)—, or —SO 2 —;  
 HET is a heterocycloalkyl ring moiety, optionally substituted with: (A) one to four —(C 1 -C 6 )alkyl, optionally substituted with one to six halogen atoms, —(C 1 -C 6 )alkoxy, cyano, halogen, hydroxy, or —NR a R b , or (B) —(C 1 -C 6 )arylalkyl, optionally substituted with one to six halogen atoms, —(C 1 -C 6 )alkoxy, cyano, halogen, hydroxy, or —NR a R b ;  
 n is 0 or 1;  
 when n is 0, X is —CH 2 —, and Y is —CH 2 —, —CHF—, or —CF 2 —;  
 or when n is 1, X is —CH 2 —, —CHF—, or —CF 2   13  ; and Y is —CH 2 —, —CHF—, or —CF 2 —, provided that X and Y are not both —CH 2 —; and  
 Z is hydrogen or cyano.  
 
     
     
         2 . The compound of  claim 1 , wherein: 
 R 1  is aryl or heteroaryl, optionally substituted independently with one to three cyano, halogen, nitro, trifluoromethyl, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —(C 3 -C 6 )cycloalkyl, or phenyl;    R 2  is —H or —(C 1 -C 6 )alkyl;    R 3  is —H or —(C 1 -C 6 )alkyl; and    HET is azetidinyl, piperazinyl, piperidinyl, pyrrolidinyl, 5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, or 7,8-dihydro-5H-pyrido[4,3-a]pyrimidin-6-yl.    
     
     
         3 . The compound of  claim 1 , wherein: 
 R 1  is benzoisothiazolyl, benzisoxazolyl, isothiazolyl, isoxazolyl, oxazolopyridyl, pyrazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, thiadiazolyl, triazinyl, or 1,1-dioxo-1H-1,2-benzoisothiazolyl;    R 2  and R 3  are —H;    Q is a covalent bond; and    HET is piperazinyl.    
     
     
         4 . The compound of  claim 3  wherein R 1  is pyridinyl or pyrimidinyl.  
     
     
         5 . The compound of  claim 4  wherein n is 1, X is —CF 2 — and Y is —CH 2 —.  
     
     
         6 . The compound of  claim 1  selected from the group consisting of 
 ((2S,4S)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrrolidin-2-yl)-(3,3-difluoropyrrolidin-1-yl)-methanone,    (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(oxazolo[5,4-b]pyridin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)-methanone,    (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(4-methylpyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)-methanone,    ((2S,4S)-4-(2-(trifluoromethy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)pyrrolidin-2-yl)-(3,3-difluoropyrrolidin-1-yl)-methanone,    ((S)-3-fluoro-pyrrolidin-1-yl)-{(2S,4S)-4-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrrolidin-2-yl}-methanone,    ((S)-3-fluoro-pyrrolidin-1-yl)-[(2S,4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrrolidin-2-yl]-methanone,    (3,3-difluoro-pyrrolidin-1-yl)-[(2S,4S)-4-(4-oxazolo[4,5-c]pyridin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone,    [(2S,4S)-4-(2-cyclopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrrolidin-2-yl]-(3-fluoro-azetidin-1-yl)-methanone,    (3,3-difluoro-pyrrolidin-1-yl)-[(2S,4S)-4-(2-ethoxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrrolidin-2-yl]-methanone,    2-{4-[(3S,5S)-5-(3-fluoro-azetidine-1-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-nicotinonitrile,    ((S)-3-fluoro-pyrrolidin-1-yl)-[(2S,4S)-4-(4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone,    (3-fluoro-azetidin-1-yl)-[(2S,4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrrolidin-2-yl]-methanone,    2-{4-[(3S,5S)-5-((S)-3-fluoro-pyrrolidine-1-carbonyl)-pyrrolidin-3-yl]-piperazin-1-yl}-nicotinonitrile,    (3-fluoro-azetidin-1-yl)-{(2S,4S)-4-[4-(2-trifluoromethyl-quinolin-4-yl)-piperazin-1-yl]-pyrrolidin-2-yl}-methanone,    ((3R*,4S*)-3,4-difluoro-pyrrolidin-1-yl)-[(2S,4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrrolidin-2-yl]-methanone, and    ((3R*,4S*)-3,4-difluoro-pyrrolidin-1-yl)-[(2S,4S)-4-(4-oxazolo[5,4-b]pyridin-2yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone; or a pharmaceutically acceptable salt of said compound.    
     
     
         7 . A compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt, for use in therapy.  
     
     
         8 . A pharmaceutical composition comprising: 
 (a) a compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt; and    (b) a pharmaceutically acceptable carrier, vehicle, diluent or excipient.    
     
     
         9 . A method of inhibiting dipeptidyl peptidase-IV in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt.  
     
     
         10 . A method of treating Type 2 diabetes in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt.  
     
     
         11 . A method of treating Type 1 diabetes in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt.  
     
     
         12 . A method of treating hyperglycemia in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt.  
     
     
         13 . A method of treating metabolic syndrome in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt.  
     
     
         14 . A method of treating impaired glucose tolerance in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt.  
     
     
         15 . A method of treating diabetic neuropathy in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt.  
     
     
         16 . A method of treating diabetic nephropathy in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt.  
     
     
         17 . A method of treating diabetic retinopathy in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt.  
     
     
         18 . A method of treating diabetic cardiomyopathy in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 ,  4  or  5 , or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt.  
     
     
         19 . The method of  claim 10  wherein said mammal is a human.